Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors

被引：22

作者：

Deng, Xinxian ^{[1
,2
]}

Shen, Jian ^{[1
,3
]}

Zhu, Hui ^{[4
]}

Xiao, Jia ^{[1
]}

Sun, Ran ^{[1
]}

Xie, Fangzhou ^{[1
]}

Lam, Celine ^{[1
]}

Wang, Juntao ^{[1
]}

Qiao, Yixue ^{[1
]}

Tavallaie, Mojdeh S. ^{[1
]}

Hu, Yang ^{[1
]}

Due, Yi ^{[5
]}

Li, Jianqi ^{[2
]}

Fu, Lei ^{[1
]}

Jiang, Faqin ^{[1
]}

机构：

[1] Shanghai Jiao Tong Univ, Sch Pharm, 800 Dongchuan Rd, Shanghai 200240, Peoples R China

[2] China State Inst Pharmaceut Ind, 285 Gebaini Rd, Shanghai 201203, Peoples R China

[3] Viva Biotech Ltd Shanghai, 334 Aidisheng Rd, Shanghai 201203, Peoples R China

[4] Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Dept Endocrinol, Sch Med, 369 Zhizaoju Rd, Shanghai 200011, Peoples R China

[5] Shanghai Jiao Tong Univ, Sch Med, Xinhua Hosp, 1665 Kongjiang Rd, Shanghai 200092, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2018年 / 26卷 / 04期

基金：

中国国家自然科学基金;

关键词：

DPP-4; inhibitor; Pyrazolo[1,5-alpha]pyrimidin-7(4H)-one derivatives; Structure-based drug design; Molecular docking; Anti-diabetic; DIPEPTIDYL-PEPTIDASE-IV; GLUCAGON-LIKE PEPTIDE-1; BIOLOGICAL EVALUATION; DISCOVERY; DERIVATIVES; OPTIMIZATION; ALOGLIPTIN; SCAFFOLD; ANALOGS;

D O I：

10.1016/j.bmc.2018.01.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC50: 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC50: 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors. (C) 2018 Elsevier Ltd. All rights reserved.

引用

页码：903 / 912

页数：10

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